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PMID:17431506

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Citation

Nelson, O, Tu, H, Lei, T, Bentahir, M, de Strooper, B and Bezprozvanny, I (2007) Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J. Clin. Invest. 117:1230-9

Abstract

Mutations in presenilins are responsible for approximately 40% of all early-onset familial Alzheimer disease (FAD) cases in which a genetic cause has been identified. In addition, a number of mutations in presenilin-1 (PS1) have been suggested to be associated with the occurrence of frontal temporal dementia (FTD). Presenilins are highly conserved transmembrane proteins that support cleavage of the amyloid precursor protein by gamma-secretase. Recently, we discovered that presenilins also function as passive ER Ca(2+) leak channels. Here we used planar lipid bilayer reconstitution assays and Ca(2+) imaging experiments with presenilin-null mouse embryonic fibroblasts to analyze ER Ca(2+) leak function of 6 FAD-linked PS1 mutants and 3 known FTD-associated PS1 mutants. We discovered that L166P, A246E, E273A, G384A, and P436Q FAD mutations in PS1 abolished ER Ca(2+) leak function of PS1. In contrast, A79V FAD mutation or FTD-associated mutations (L113P, G183V, and Rins352) did not appear to affect ER Ca(2+) leak function of PS1 in our experiments. We validated our findings in Ca(2+) imaging experiments with primary fibroblasts obtained from an FAD patient possessing mutant PS1-A246E. Our results indicate that many FAD mutations in presenilins are loss-of-function mutations affecting ER Ca(2+) leak activity. In contrast, none of the FTD-associated mutations affected ER Ca(2+) leak function of PS1, indicating that the observed effects are disease specific. Our observations are consistent with the potential role of disturbed Ca(2+) homeostasis in Alzheimer disease pathogenesis.

Links

PubMed PMC1847535 Online version:10.1172/JCI30447

Keywords

Alzheimer Disease/genetics; Alzheimer Disease/metabolism; Amino Acid Substitution/genetics; Animals; Calcium Channels/genetics; Calcium Channels/metabolism; Calcium Signaling/genetics; Cell Line; Endoplasmic Reticulum/genetics; Endoplasmic Reticulum/metabolism; Female; Humans; Male; Mice; Middle Aged; Mutagenesis, Site-Directed; Presenilin-1/genetics; Presenilin-1/physiology; Spodoptera

Significance

Annotations

Gene product Qualifier GO ID GO term name Evidence Code with/from Aspect Notes Status


See also

References

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